Nearly 200,000 people in the U.S. live with a disability related to a spinal cord injury (SCI). SCI occurs when axons or nerve fibers of the spinal cord are interrupted, generally by mechanical forces. If the spinal cord is compressed, severed or contused, the axons may be physically or physiologically disintegrated so that no conduction of neuroelectric impulses can occur along the affected axon's length. Eventually, large populations of axons including their associated cell bodies may die, causing massive loss in communications between the brain and the peripheral nerves, and resulting in varying degrees of paraplegia or quadriplegia.
Typically, the treatment for SCI involves promoting neurological survival and axonal sprouting using neurotrophic and growth factors at the lesion site. Massive neural cell death occurring after SCI plays a critical role in the progress of secondary neurological damage. Thus, neuroprotective strategies to inhibit cell death and axonal dysfunction can decrease further functional loss after SCI. Among these strategies, application of neurotrophins and anti-inflammatory factors has shown promising effects on improving neuroprotection.
One problem that causes the failure of CNS neuron regeneration is inhibition of neurite outgrowth by certain bioactive molecules. Myelin contributes to a number of proteins that have shown to inhibit neurite process outgrowth. NogoA is the first protein identified on the surface of the oligodendrocytes and some axons. Other proteins that can contribute to inhibition include myelin-associated glycoprotein (MAG), oligodendrocyte-myelin glycoprotein (OMgp) and the proteoglycan versican.
The other source of major inhibitory activity lies with the formation of a glial scar after CNS injury. The scarring process involves a number of cells that can upregulate the synthesis and secretion of chondroitin sulfate proteoglycans (CSPG). CSPG accumulation occurs very rapidly at the lesion site, generally within one week post injury. It is believed that large glycosaminoglycan (GAG) sugar side chain within the CSPG are responsible for major inhibitory effects on axon elongation, by blocking access to growth promoting factors. It has also been demonstrated both in vitro and in vivo that axons can grow on a CSPG substrate if the GAG is removed by chondroitinase ABC (cABC) cleavage.
SCI presents an extreme set of problems to overcome to promote healing and reinnervation as many of the inhibitory molecules for the nerve regeneration appear at different stages post SCI. An effective treatment usually requires accommodating the dynamic changes in the microenvironment of the lesion site following SCI.
A previously unaddressed need exists in the art to address the deficiencies and inadequacies, especially in connection with provision of a formulation for releasing available therapeutic agents in a time-dependent sequential manner at the lesion site.